Targeting Bcl-2 protein in treatment of melanoma still requires further clarifications.

In recent past years, addition of oblimersen (G3139; Genta International Inc., NJ), an antisense oligonucleotide downregulating Bcl-2 expression, to a dacarbazine-based chemotherapy for the treatment of advanced melanoma has increased tumor-cell apoptosis in a phase I-II study [2] and improved overall survival in patients with normal serum lactate dehydrogenase in a randomized phase III clinical trial [3]. However, questions arise over the cause- effect relationship between the antiproliferative activity of oblimersen and somatic expression levels of the Bcl-2 protein.In the light of recent advances, it appears evident that targeting a single component within the multiple signaling pathways involved in development and progression of human cancers is unlikely to yield significant antitumor responses. More in general, making correlations between functionally associated molecular signatures and clinical response to therapy may avoid that targeted treatments in patients carrying one specific molecular alteration achieve different clinical outcomes due to the coexistence of additional alterations in alternative pathways. For sure, the introduction of targeted therapies is generating more questions than answers.